| Antibody-drug conjugates (ADCs) achieve precise delivery of cytotoxic payloads through the specific targeting of monoclonal antibodies, demonstrating significant clinical value in recent years for treating various refractory malignancies such as triple-negative breast cancer, small cell lung cancer, and urothelial carcinoma. However, ADC efficacy varies from different patients, necessitating the identification of optimal beneficiary populations. Current biomarker research primarily focuses on target antigen expression levels, while systematic investigations into other potential predictive indicator, including tumor genomic profiles, endocytosis-related proteins, drug transporter activity, and tumor microenvironment immune characteristics, remain inadequate. Furthermore, ADC resistance is inevitable, with underlying mechanisms involving dysfunction across multiple critical processes, which include reduced target antigen-mediated internalization efficiency, aberrant lysosomal degradation, payload resistance, and immune regulatory dysfunction. To address these challenges, contemporary research has proposed three major resistance-overcoming strategies: developing ADC-based combination therapies, designing novel ADC constructs, and optimizing dosing regimens. This review systematically summarizes recent advances in ADC biomarker research, current understanding of resistance mechanisms, and corresponding strategies to overcome resistance, thereby providing theoretical foundations and practical guidance for future basic and translational clinical investigations. |
